Structure-based virtual screening and discovery of New PPARδ/γ dual agonist and PPARδ and γ agonists.

Vinicius G Maltarollo,Alessandro S Nascimento,Marie Togashi,Kathia M Honorio,Paul Taylor

doi:10.1371/journal.pone.0118790

Abstract

Peroxisome proliferator-activated receptors (PPARs) are involved in the control of carbohydrate and lipid metabolism and are considered important targets to treat diabetes mellitus and metabolic syndrome. The available PPAR ligands have several side effects leading to health risks justifying the search for new bioactive ligands to activate the PPAR subtypes, in special PPARδ, the less studied PPAR isoform. Here, we used a structure-based virtual screening protocol in order to find out new PPAR ligands. From a lead-like subset of purchasable compounds, we identified 5 compounds with potential PPAR affinity and, from preliminary in vitro assays, 4 of them showed promising biological activity. Therefore, from our in silico and in vitro protocols, new PPAR ligands are potential candidates to treat metabolic diseases.

Highlights

Peroxisome proliferator-activated receptors (PPARs) constitute a subfamily of nuclear receptors involved in the transcription of genes related to the cellular proliferation and differentiation, immune responses and metabolism of carbohydrates and lipids [1,2,3,4,5,6,7,8]
From the 21 crystallographic structures of PPARδ [27,55,56,57,58,59,60,61,62,63,64,65,66,67,68] found in Protein Data Bank (PDB), we selected the structure with PDB code 3GZ9 [27] due to its crystallographic quality and the similarity of its crystallographic ligand to the compound dataset employed in the enrichment-based model calibration stage
740,000 compounds were docked in the active site of PPARδ using the program UCSF DOCK 3.5.54 [29,30,31,32,33,34,35] and, they were sorted from the calculated binding energy

Summary

Introduction

Peroxisome proliferator-activated receptors (PPARs) constitute a subfamily of nuclear receptors involved in the transcription of genes related to the cellular proliferation and differentiation, immune responses and metabolism of carbohydrates and lipids [1,2,3,4,5,6,7,8]. From the pathological point of view, these receptors are related to metabolic diseases (mainly, type 2 diabetes mellitus, metabolic syndrome and dyslipidemia) [9,10,11], inflammatory process [12,13], neurodegeneration [14] and some kinds of cancer [15,16,17]. The treatment of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS) brings an important focus to the development of new PPAR agonists. There are at least two classes of pharmacological agents targeting the PPARs. The fibrates are known as PPARα ligands used for the control of hypercholesterolemia, while the thiazolidinediones (TZDs) such as rosiglitazone and pioglitazone are PPARγ full agonists used as insulin sensitizers in T2DM therapy. Despite the clear efficacy to restore blood glucose levels, rosiglitazone was reported to cause important side effects, such as fluid retention, weight gain and increase in the chance of a PLOS ONE | DOI:10.1371/journal.pone.0118790 March 13, 2015

Methods

Results

Conclusion